Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Syntheses of the enantiomers of myo-inositol 1,3,4-trisphosphate are described. 1,4-Di-O-allyl-myo-inositol was regioselectively p-methoxybenzylated at the 3-position to give 1,4-di-O-allyl-3-O-(p-methoxybenzyl)-myo-inositol followed by benzylation of the remaining free hydroxyl groups to give the key intermediate 1,4-di-O-allyl-2,5,6-tri-O-benzyl-3-O-(p-methoxybenzyl)-myo-inositol. Removal of the p-methoxybenzyl and allyl groups gave 2,4,5-tri-O-benzyl-myo-inositol which was phosphitylated with bis(benzyloxy)(diisopropylamino)phosphine to give the fully protected trisphosphite triester. Oxidation using tert-butyl hydroperoxide gave 2,5,6-tri-O-benzyl-1,3,4-tris(dibenzylphospho)-myo-inositol, and deprotection using sodium in liquid ammonia gave racemic myo-inositol 1,3,4-trisphosphate. Deprotection of the key intermediate 1,4-di-O-allyl-2,5,6-tri-O-benzyl-3-O-(p-methoxybenzyl)-myo-inositol by isomerization of allyl groups followed by mild acid hydrolysis gave 2,4,5-tri-O-benzyl-1-O-(p-methoxybenzyl)-myo-inositol, which was converted to the diastereoisomeric (bis-(-)-camphanates. The diastereoisomers were separated by column chromatography and the camphanates and the p-methoxybenzyl group removed by saponification and acid hydrolysis, respectively, for each diastereoisomer to give the enantiomers of 2,4,5-tri-O-benzyl-myo-inositol. The absolute configurations of the latter were established by conversion of 1L-2,5,6-tri-O-benzyl-3-O-(p-methoxybenyl)-myo-inositol to the known 1L-1,2,4,5,6-penta-O-benzyl-myo-inositol. Phosphorylation and deblocking gave the D- and L-enantiomers of myo-inositol 1,3,4-trisphosphate. Biological evaluation in Limulus photoreceptors showed that 1L-myo-inositol 1,3,4-trisphosphate was much more active than the D-enantiomer, producing repetitive bursts of depolarization due to mobilization of intracellular calcium.

Type

Journal article

Journal

J Med Chem

Publication Date

11/11/1994

Volume

37

Pages

3918 - 3927

Keywords

Animals, Calcium, Horseshoe Crabs, Inositol Phosphates, Photoreceptor Cells, Invertebrate, Stereoisomerism